Affinage

SMCR8

Guanine nucleotide exchange protein SMCR8 · UniProt Q8TEV9

Length
937 aa
Mass
105.0 kDa
Annotated
2026-06-10
18 papers in source corpus 14 papers cited in narrative 15 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SMCR8 is a DENN-domain protein that functions as the catalytic subunit of a stable trimeric complex with C9orf72 and WDR41, governing autophagy-lysosomal homeostasis and membrane trafficking (PMID:27193190, PMID:27617292, PMID:27559131, PMID:32303654). Within this complex SMCR8 binds C9orf72 and WDR41 — the latter engaging the SMCR8 DENN domain via its C-terminal helix — to form a dimer of heterotrimers in which SMCR8 contributes a critical arginine finger (Arg147) for GTPase-activating protein (GAP) activity toward RAB8A and RAB11A (PMID:32303654); C9orf72 serves as the RAB8A-binding subunit (PMID:38064514). Through this GAP activity the complex restrains primary ciliogenesis and hedgehog responsiveness (PMID:38064514) and drives RAB8A-dependent, ESCRT-mediated lysosomal repair in microglia, where loss of function leads to accumulation of hyperphosphorylated, mislocalized GTP-bound RAB8A (PMID:42215790). The complex localizes to lysosomes and acts upstream of mTORC1, and SMCR8 also associates with the FIP200/ULK1 autophagy-initiation complex through a coiled-coil platform in its uDENN domain (PMID:27193190, PMID:27617292, PMID:27559131, PMID:34297726). SMCR8 stabilizes C9orf72 protein, so its loss reduces C9orf72 levels, hyperactivates mTORC1/AKT, impairs autophagy and lysosomal degradation, and increases lysosomal exocytosis (PMID:29950492, PMID:30696333, PMID:31847700). In mice, SMCR8 deficiency causes prolonged endosomal TLR3/7/9 signaling and inflammatory disease, motor-neuron axonal pathology and behavioral deficits, and exacerbates C9ALS/FTD pathology (PMID:30442666, PMID:31625563). SMCR8 itself is poly-ubiquitinated and localizes to stress granules, and an SMCR8 isoform is targeted for proteasomal degradation by the CRL2FEM1B E3 ligase through a C-degron (PMID:32678027, PMID:33892462).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2016 High

    Establishing SMCR8's core molecular context: it was unknown what SMCR8 does, and identifying it as a stable partner of C9orf72 and WDR41 that docks onto the FIP200/ULK1 autophagy machinery placed SMCR8 directly in the autophagy-initiation pathway.

    Evidence Reciprocal co-immunoprecipitation and interaction mapping across multiple labs

    PMID:27193190 PMID:27559131 PMID:27617292

    Open questions at the time
    • Stoichiometry and architecture of the complex not yet resolved
    • Catalytic activity of SMCR8 within the complex undefined
  2. 2016 Medium

    The first enzymatic assignment proposed the complex as a GEF for RAB39B, addressing whether the complex acts on Rab GTPases, but this nucleotide-exchange role was later overturned by structural GAP findings.

    Evidence In vitro GTPase and GEF biochemical assays, single lab

    PMID:27617292

    Open questions at the time
    • GEF assignment contradicted by subsequent GAP studies
    • Substrate identity (RAB39B vs RAB8A/RAB11A) not reconciled at the time
  3. 2016 Medium

    Linking SMCR8 to cellular function showed that its loss impairs autophagy induction and reduces ULK1, and positions the C9orf72-SMCR8 complex at lysosomes upstream of amino-acid-regulated mTORC1 signaling.

    Evidence Smcr8 KO mice, autophagy flux assays, KO cell lines with mTORC1 readouts and microscopy

    PMID:27559131 PMID:27617292

    Open questions at the time
    • Molecular link between the complex and mTORC1 regulation undefined
    • Whether autophagy defect is direct or secondary to lysosomal dysfunction unclear
  4. 2018 Medium

    Defining the interdependence of complex subunits, SMCR8 was shown to stabilize C9orf72 protein and to restrain lysosomal exocytosis in macrophages, establishing that SMCR8 loss reshapes lysosomal output.

    Evidence Quantitative MS proteomics, Smcr8 KO mice, flow cytometry for surface LAMP1

    PMID:29950492

    Open questions at the time
    • Mechanism by which SMCR8 stabilizes C9orf72 not defined
    • Direct trafficking substrate driving exocytosis not identified
  5. 2018 High

    Causally connecting the lysosomal defect to disease, SMCR8 loss was shown to delay phagosome maturation and prolong endosomal TLR signaling, with triple TLR3/7/9 knockout rescuing the inflammatory phenotype.

    Evidence Smcr8 KO mice, genetic epistasis via TLR3/7/9 triple-KO rescue, cytokine and LysoTracker assays

    PMID:30442666

    Open questions at the time
    • How lysosomal dysfunction mechanistically sustains TLR signaling not resolved
    • Relevant Rab substrate in phagosome maturation not pinpointed
  6. 2019 Medium

    Multiple in vivo studies converged on signaling and neuronal consequences, showing SMCR8 loss lowers C9orf72, hyperactivates mTORC1/AKT, downregulates autophagy-lysosomal proteins, and produces motor-neuron axonal pathology that worsens C9ALS/FTD models.

    Evidence Smcr8 KO and haploinsufficiency mice, double KO with rapamycin rescue, western blots, neuronal morphology, axonal transport and behavioral assays

    PMID:30696333 PMID:31625563 PMID:31847700

    Open questions at the time
    • Direct molecular trigger of mTORC1 hyperactivation not isolated
    • Cell-autonomy of motor-neuron phenotype not fully resolved
  7. 2020 High

    Structural determination redefined the complex's enzymology: cryo-EM revealed a dimer of heterotrimers and identified SMCR8 Arg147 as the arginine finger driving GAP activity toward RAB8A and RAB11A, replacing the earlier GEF model.

    Evidence 3.2 Å cryo-EM structure, Arg147 mutagenesis, in vitro GAP biochemical assay

    PMID:32303654

    Open questions at the time
    • Physiological selectivity among Rab substrates in vivo not established
    • Regulation of GAP activity by complex assembly not defined
  8. 2020 Medium

    Characterizing SMCR8's own regulation and localization, it was found to be poly-ubiquitinated without rapid degradation, to localize to stress granules, and to interact broadly with the ubiquitin-proteasome system.

    Evidence MS interactome, ubiquitination assay, immunofluorescence

    PMID:32678027

    Open questions at the time
    • Functional consequence of stress-granule localization unknown
    • Ubiquitin ligase responsible not identified in this study
  9. 2021 High

    Two studies refined complex architecture and SMCR8 turnover: a coiled-coil in the uDENN domain was identified as a dimerization and FIP200-interaction platform, and CRL2FEM1B was shown to recognize a C-degron on an SMCR8 isoform.

    Evidence 3.8 Å cryo-EM, deletion mutagenesis with starvation Co-IP; structural and biochemical C-degron recognition of FEM1B-SMCR8

    PMID:33892462 PMID:34297726

    Open questions at the time
    • Physiological conditions controlling CRL2FEM1B-mediated SMCR8 degradation unclear
    • Which SMCR8 isoform is degron-bearing in vivo not established
  10. 2023 High

    Dissecting subunit roles in a defined pathway, the complex was shown to negatively regulate primary ciliogenesis as a RAB8A GAP, with C9orf72 binding RAB8A and SMCR8 supplying GAP activity, and loss sensitizing cells to hedgehog signaling.

    Evidence Biochemical GAP assay with subunit dissection, KO cells and mice, cilia and hedgehog reporter assays

    PMID:38064514

    Open questions at the time
    • How ciliary RAB8A inactivation is spatially controlled not defined
    • Contribution of RAB11A to this process not addressed
  11. 2024 High

    Connecting GAP activity to lysosomal quality control, the complex was shown to enable RAB8A-ESCRT-mediated lysosomal repair in microglia, where loss causes accumulation of hyperphosphorylated, mislocalized GTP-bound RAB8A and failed ESCRT recruitment.

    Evidence C9orf72/Smcr8 KO mice, LLOMe lysosomal damage and galectin-3 assays, ESCRT recruitment and RAB8A GTP-loading assays

    PMID:42215790

    Open questions at the time
    • Kinase responsible for RAB8A hyperphosphorylation not identified
    • Direct molecular link between RAB8A state and ESCRT recruitment not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SMCR8/C9orf72 GAP activity toward RAB8A/RAB11A is spatially and temporally coordinated across distinct membrane events (ciliogenesis, phagosome maturation, lysosomal repair, exocytosis) and how this integrates with mTORC1 control remains unresolved.
  • No unified model linking the single GAP activity to its many membrane-trafficking outputs
  • Mechanism of mTORC1 hyperactivation downstream of complex loss not pinned to a substrate

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 3 GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005764 lysosome 2 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-9612973 Autophagy 2 R-HSA-168256 Immune System 1
Partners
C9ORF72FEM1BFIP200RAB11ARAB8AULK1WDR41
Complex memberships
C9orf72-SMCR8-WDR41 complexCRL2FEM1B (substrate)

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 SMCR8 forms a heterodimer with C9orf72 and together they bind WDR41 to form a trimeric complex; this complex associates with the FIP200/ULK1 autophagy-initiation complex Co-immunoprecipitation, protein interaction mapping Acta neuropathologica communications High 27193190 27559131 27617292
2016 The C9ORF72-SMCR8 complex displays GTPase activity and acts as a guanine nucleotide exchange factor (GEF) for RAB39B GTPase activity assay, GEF biochemical assay Science advances Medium 27617292
2016 SMCR8 loss-of-function impairs autophagy induction and reduces ULK1 expression and activity; SMCR8/C9ORF72 interacts with the ULK1 complex to regulate it Smcr8 knockout mice, autophagy flux assays, western blotting for ULK1 Science advances Medium 27617292
2016 C9orf72 localizes to lysosomes in a manner negatively regulated by amino acid availability; SMCR8 KO impairs mTORC1 signaling responses to amino acid availability, placing the C9orf72-SMCR8 complex at lysosomes upstream of mTORC1 Genome-edited KO cell lines, fluorescence microscopy, mTORC1 signaling assays Molecular biology of the cell Medium 27559131
2018 SMCR8 stabilizes C9orf72 protein (the long isoform complexes with and stabilizes SMCR8, which further enables WDR41 interaction); SMCR8 loss increases lysosomal exocytosis in macrophages, evidenced by elevated surface LAMP1 and enhanced secretion of lysosomal components Quantitative mass spectrometry proteomics, Smcr8 KO mice, flow cytometry for surface LAMP1 Genes & development Medium 29950492
2018 Loss of SMCR8 causes accumulation of LysoTracker-positive vesicles and delayed phagosome maturation in macrophages, leading to prolonged endosomal TLR signaling and inflammatory disease; this inflammatory phenotype is rescued by triple knockout of TLR3/7/9 Smcr8 KO mice, genetic epistasis (triple TLR3/7/9 KO rescue), cytokine assays, LysoTracker staining Proceedings of the National Academy of Sciences of the United States of America High 30442666
2019 SMCR8 ablation in mice leads to decreased C9orf72 protein levels, elevated MTORC1 and AKT activation, downregulation of autophagy-lysosomal pathway proteins, and increased spine density in neurons Smcr8 KO mice, western blotting for mTORC1/AKT substrates, neuronal morphology analysis Autophagy Medium 30696333
2019 In terminally differentiated (c9orf72 or smcr8 mutant) macrophages, impaired lysosomal degradation and exocytosis cause autolysosome acidification defects, resulting in aberrant upregulation of MTOR protein and MTORC1 hyperactivation; rapamycin treatment partially rescues macrophage dysfunction and splenomegaly c9orf72/smcr8 single and double KO mice, pharmacological mTORC1 inhibition rescue, lysosomal pH assays Autophagy Medium 31847700
2019 Smcr8 deficiency impairs axonal transport-dependent autophagy-lysosomal function in motor neurons, causing axonal swellings in spinal cord and neuromuscular junctions and motor behavior deficits; Smcr8 haploinsufficiency exacerbates pathology in C9ALS/FTD mouse models Smcr8 KO mice, behavioral assays, histopathology, axonal transport assays in motor neurons Human molecular genetics Medium 31625563
2020 Cryo-EM structure of the C9ORF72-SMCR8-WDR41 complex at 3.2 Å reveals a dimer of heterotrimers; within the heterotrimer, SMCR8 joins C9ORF72 and WDR41 without direct C9ORF72-WDR41 contact; WDR41 binds the DENN domain of SMCR8 via its C-terminal helix; the complex acts as a GAP for RAB8A and RAB11A, with Arg147 of SMCR8 serving as the critical arginine finger Cryo-EM structure determination (3.2 Å), mutagenesis of Arg147, in vitro GAP biochemical assay Proceedings of the National Academy of Sciences of the United States of America High 32303654
2020 SMCR8 is poly-ubiquitinated without obvious degradation, and endogenous SMCR8 protein localizes to cytoplasmic stress granules; SMCR8 interacts with many components of the ubiquitin-proteasome system Mass spectrometry interactome, ubiquitination assay, immunofluorescence localization to stress granules Acta neuropathologica communications Medium 32678027
2021 CRL2FEM1B E3 ligase recognizes a C-degron on an SMCR8 isoform via FEM1B; crystal/structural analysis of the FEM1B-SMCR8 complex reveals the molecular basis of this recognition, defining CRL2FEM1B as a regulator of SMCR8 protein lifetime Structural analysis of FEM1B-SMCR8 complex, biochemical C-degron recognition assay Biochemical and biophysical research communications Medium 33892462
2021 Cryo-EM structure of the C9orf72-SMCR8 complex at 3.8 Å reveals two distinct dimerization interfaces; a coiled-coil region in the uDENN domain of SMCR8 acts as an interaction platform, and its deletion reduces interaction of the complex with FIP200 upon starvation Single-particle cryo-EM (3.8 Å), deletion mutagenesis, Co-IP under starvation conditions PLoS biology High 34297726
2023 The C9orf72-SMCR8 complex negatively regulates primary ciliogenesis as a RAB8A GAP; C9orf72 is the RAB8A-binding subunit and SMCR8 is the GAP subunit; loss of either component sensitizes cells to hedgehog signaling Biochemical GAP assay, KO cell lines, cilia formation assay, hedgehog signaling reporter, in vivo tissue analysis in KO mice Proceedings of the National Academy of Sciences of the United States of America High 38064514
2024 The C9orf72/SMCR8 complex maintains microglial lysosomal homeostasis via RAB8A-ESCRT-mediated lysosomal repair; loss of C9orf72/SMCR8 causes accumulation of GTP-bound (active) RAB8A that becomes hyperphosphorylated and mislocalizes to RAB7+/LAMP1− vesicles; the GAP activity of the complex is essential for ESCRT recruitment and lysosomal repair C9orf72/Smcr8 KO mice, lysosomotropic agent (LLOMe) lysosomal damage assay, galectin-3 puncta assay, ESCRT recruitment assay, RAB8A GTP-loading assay The EMBO journal High 42215790

Source papers

Stage 0 corpus · 18 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 The ALS/FTLD associated protein C9orf72 associates with SMCR8 and WDR41 to regulate the autophagy-lysosome pathway. Acta neuropathologica communications 237 27193190
2016 A C9ORF72/SMCR8-containing complex regulates ULK1 and plays a dual role in autophagy. Science advances 190 27617292
2016 C9orf72 binds SMCR8, localizes to lysosomes, and regulates mTORC1 signaling. Molecular biology of the cell 149 27559131
2020 Cryo-EM structure of C9ORF72-SMCR8-WDR41 reveals the role as a GAP for Rab8a and Rab11a. Proceedings of the National Academy of Sciences of the United States of America 61 32303654
2018 The C9orf72-interacting protein Smcr8 is a negative regulator of autoimmunity and lysosomal exocytosis. Genes & development 56 29950492
2018 Excessive endosomal TLR signaling causes inflammatory disease in mice with defective SMCR8-WDR41-C9ORF72 complex function. Proceedings of the National Academy of Sciences of the United States of America 47 30442666
2019 C9orf72 and smcr8 mutant mice reveal MTORC1 activation due to impaired lysosomal degradation and exocytosis. Autophagy 45 31847700
2019 SMCR8 negatively regulates AKT and MTORC1 signaling to modulate lysosome biogenesis and tissue homeostasis. Autophagy 26 30696333
2020 C9orf72-associated SMCR8 protein binds in the ubiquitin pathway and with proteins linked with neurological disease. Acta neuropathologica communications 16 32678027
2019 Smcr8 deficiency disrupts axonal transport-dependent lysosomal function and promotes axonal swellings and gain of toxicity in C9ALS/FTD mouse models. Human molecular genetics 16 31625563
2021 Structural insights into SMCR8 C-degron recognition by FEM1B. Biochemical and biophysical research communications 14 33892462
2020 The C9orf72-SMCR8-WDR41 complex is a GAP for small GTPases. Autophagy 12 32521185
2017 Multifaceted role of SMCR8 as autophagy regulator. Small GTPases 10 28696821
2023 ALS-linked C9orf72-SMCR8 complex is a negative regulator of primary ciliogenesis. Proceedings of the National Academy of Sciences of the United States of America 8 38064514
2021 Structure of the human C9orf72-SMCR8 complex reveals a multivalent protein interaction architecture. PLoS biology 8 34297726
2024 The C9orf72-SMCR8 complex suppresses primary ciliogenesis as a RAB8A GAP. Autophagy 6 38293807
2021 Molecular interactions between C9ORF72 and SMCR8: A local energetic frustration perspective. Biochemical and biophysical research communications 3 34256240
2026 The C9orf72/SMCR8 complex maintains microglial homeostasis via RAB8A-ESCRT-mediated lysosomal repair. The EMBO journal 0 42215790

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